While the immune system plays a crucial role in protecting higher organisms against life-threatening infections, the immune system also plays a crucial part in the pathogenesis of numerous diseases. Those diseases in which the immune system plays a part include autoimmune diseases in which the immune system reacts against an autologous antigen, e.g., systemic lupus erythematosus, or diseases associated with immunoregulation initiated by reaction to a foreign antigen, e.g., graft vs. host disease observed in transplantation rejection.
The pathogenesis and exacerbation of many common T-cell mediated diseases result from an inappropriate immune response driven by abnormal T-cell activation. The presence of activated T-cells have been reported in many T-cell mediated skin diseases (Simon et al., (1994) J. Invest Derm., 103:539-543). For example, psoriasis, which afflicts 2% of the Western population including four million Americans, is a skin disorder characterized by keratinocyte hyperproliferation and abnormal dermal and epidermal infiltration of activated T-cells. Many reports suggest a major role of these activated T-cells in the pathogenesis of psoriasis (Baadsgaard et al., (1990) J. Invest Derm., 95:275-282, Chang et al., (1992) Arch. Derm., 128:1479-1485, Schlaak et al., (1994) J. Invest Derm., 102:145-149) and in AIDS-exacerbated psoriasis (Duvic (1990) J. Invest. Derm., 90:38S-40S). In psoriasis, activated lesional T-cells predominantly release the Th1 cytokines (IL-2, interferon-gamma) (Schlaak et al., (1994) J. Invest Derm., 102:145-149). These secreted cytokines induce normal keratinocytes to express the same phenotype (HLA DR+/ICAM-1+) as found in psoriasis lesions (Baadsgaard et al., (1990) J. Invest Derm., 95:275-282). Also, by virtue of its in vitro and in vivo proinflammatory properties and because it is secreted in large amounts by both activated T-cells and keratinocytes from psoriatic lesions, IL-8 is considered to be a major contributor to the pathologic changes seen in psoriatic skin such as keratinocyte hyperproliferation. Furthermore, one of the B7 family of receptors (the natural ligands for CD28 found on activated APC), BB1, has been shown to be expressed in psoriatic but not unaffected skin keratinocytes (Nickoloff, et al., (1993) Am. J. Pathology, 142:1029-1040).
A number of other diseases are thought to be caused by aberrant T-cell activation, including Type I (insulin-dependent) diabetes mellitus, thyroiditis, sarcoidosis, multiple sclerosis, autoimmune uveitis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease (Crohn's and ulcerative colitis) and autoimmune hepatitis. In addition, a variety of syndromes including septic shock and tumor-induced cachexia may involve T-cell activation and augmented production of potentially toxic levels of lymphokines. Normal T-cell activation also mediates the rejection of transplanted cells and organs by providing the necessary signals for the effective destruction of the "foreign" donor tissue.
The activation of T-lymphocytes leading to T-cell proliferation and gene expression and secretion of specific immunomodulatory cytokines requires two independent signals. The first signal involves the recognition, by specific T-cell receptor/CD3 complex, of antigen presented by major histocompatibility complex molecules on the surface of antigen presenting cells (APCs). Antigen-nonspecific intercellular interactions between T-cells and APCs provide the second signal that serves to regulate T-cell responses to antigen. These secondary or costimulatory signals determine the magnitude of a T-cell response to antigen. Costimulated cells react by increasing the levels of specific cytokine gene transcription and by stabilizing selected mRNAs. In the absence of costimulation, T-cell activation results in an aborted or anergic T-cell response. One key costimulatory signal is provided by interaction of the T-cell surface receptor CD28 with B7-related molecules on APC (Linsley and Ledbetter (1993) Ann. Rev. Immunol., 11:191-212). CD28 is constitutively expressed on 95% of CD4+ T-cells (which provide helper functions for B-cell antibody production) and 50% of CD8+ T-cells (which have cytotoxic functions) (Yamada et al., (1985) Eur. J. Immunol. 15:1164-1168). Following antigenic or in vitro mitogenic stimulation, further induction of surface levels of CD28 occurs, as well as the production of certain immunomodulatory cytokines. These include interleukin-2 (IL-2), required for cell cycle progression of T-cells, interferon-gamma, which displays a wide variety of anti-viral and anti-tumor effects and interleukin-8 (IL-8), known as a potent chemotactic factor for neutrophils and lymphocytes. These cytokines have been shown to be regulated by the CD28 pathway of T-cell activation (Fraser et al., (1991) Science, 251:313-316, Seder et al., (1994) J. Exp. Med., 179:299-304, Wechsler et al., (1994) J. Immunol., 153:2515-2523). IL-2, interferon-gamma, and IL-8 are essential in promoting a wide range of immune responses and have been shown to be overexpressed in many T-cell mediated disease states.
In some T-cell mediated skin disorders such as allergic contact dermatitis and lichen planus, CD28 was expressed in high levels in the majority of dermal and epidermal CD3+ T-cells but in normal skin and basal cell carcinoma (a non T-cell mediated skin disease), CD28 was expressed only in perivascular T-cells. Similarly, in both allergic contact dermatitis and lichen planus, B7 expression was found on dermal dendritic cells, dermal APCs and on keratinocytes but not in normal skin and basal cell carcinoma (Simon et al., (1994) J. Invest Derm., 103:539-543). Therefore this suggests that the CD28/B7 pathway is an important mediator of T-cell-mediated skin diseases.
Aberrant T-cell activation associated with certain autoimmune diseases caused by the loss of self-tolerance is predominantly characterized by the presence of CD28+ T-cells and expression of its ligand, B7 on activated professional APCs (monocyte, macrophage or dendritic cells). These include autoimmune Graves thyroiditis (Garcia-Cozar et al., (1993) Immunol., 12:32), sarcoidosis (Vandenbergh et al., (1993) Int. Immunol., 5:317-321), rheumatoid arthritis (Verwilghen et al. (1994) J. Immunol., 153:1378-1385) and systemic lupus erythematosus (Sfikakis et al., (1994) Clin. Exp. Immunol., 96:8-14). In normal T-cell activation, which mediates the rejection of transplanted cells and organs, the binding of CD28 by its appropriate B7 ligand during T-cell receptor engagement is critical for proper allogeneic response to foreign antigens, for example, on donor tissue (Azuma et al., (1992) J. Exp. Med., 175:353-360, Turka et al., (1992) Proc. Nat. Acad. Sci. USA, 89:11102-11105).
Traditional therapies for autoimmune diseases do not prevent T-cell activation; the effector step in the autoreactive immune responses to self-antigen. Drugs, such as steroids and non-steroid anti-inflammatory drugs (NSAIDS), are currently used to ameliorate symptoms, but they do not prevent the progression of the disease. In addition, steroids can have side effects such as inducing osteoporosis, organ toxicity and diabetes, and can accelerate the cartilage degeneration process and cause so-called post-injection flares for up to 2 to 8 hours. NSAIDS can have gastrointestinal side effects and increase the risk of agranulocytosis and iatrogenic hepatitis. Immunosuppressive drugs are also used as another form of therapy, especially in advanced disease stages. However, these drugs suppress the entire immune system and often treatment has severe side effects including hypertension and nephrotoxicity. Also established immunosuppressants such as cyclosporin and FK506 cannot inhibit the CD28-dependent T-cell activation pathway (June et al., (1987) Mol. Cell. Biol., 7:4472-4481).
Given the shortcomings of currently-available pharmaceuticals and methods for treating immune system-mediated diseases, it is of interest to provide new methods and compositions for treating such diseases.